PROJECT SUMMARY/ABSTRACT Little is known about the epidemiology of Alzheimer?s disease (AD) in populations living pre-industrial lifestyles similar to those experienced over human pre-history. This information is critical to determine whether AD is a byproduct of modern environments. Compared to age- matched industrialized populations, Tsimane exhibit: a) delayed atherosclerosis progression; b) minimal diabetes and hypertension; and c) near absence of atrial fibrillation, stroke and myocardial infarction. At the same time, Tsimane experience high infectious burden and resulting inflammation throughout life. The neighboring Moseten are an ethnolinguistically similar population with low cardiovascular disease (CVD) risk, as indicated by our preliminary data, but Moseten have both higher rates of CVD than Tsimane and more variation in lifestyle and metabolic risk factors. The goals of this proposal are to: 1) Measure rates of cerebral atrophy and cognitive decline in association with atherosclerotic and inflammatory burden, APOE genotype, and schooling among Tsimane and Moseten; and 2) Estimate prevalence and incidence of all-cause dementia and AD among Tsimane and Moseten. Our central motivating hypothesis is that compared to Western populations, the low rate of atherosclerosis in these two subsistence populations will be paralleled by slower rates of cerebral atrophy and age-related cognitive impairment. To accomplish our goals, we propose four specific aims, utilizing a panel design in two population samples totaling 2,590 adults aged 40+ years: 1,963 Tsimane and 627 Moseten. Aim 1 conducts longitudinal assessment of cognitive impairment and dementia with measurement of physical activity between assessments; Aim 2 conducts anatomic neuroimaging of the brain related to cognitive impairment, AD and other dementias; Aim 3 assesses prevalence and incidence of all-cause dementia and AD among individuals over age 60 years; and Aim 4 investigates the epidemiology of brain atrophy, cognitive impairment, AD and all-cause dementia. The proposed research is time-sensitive, as both Tsimane and Moseten are modernizing at an accelerating rate. It is one of our last chances to study the natural history of AD, cerebral atrophy and cognitive impairment with a large sample across multiple populations living a subsistence lifestyle, similar to pre-historic populations, with low rates of CVD and high rates of infectious disease and inflammation. This multi-disciplinary project leverages 14 years of integrated behavioral-biomedical research among Tsimane. If rates of cerebral atrophy and cognitive impairment are lower among aging Tsimane and Moseten, those findings will have important implications for our understanding of AD in the US.